Clozapine is an FDA-approved atypical antipsychotic for treatment-resistant schizophrenia. The definition of treatment-resistant schizophrenia is persistent or moderate delusions or hallucinations after failing 2 trials of antipsychotic medicines. Since its creation, it has been the drug of choice for treatment-resistant schizophrenia, even though it has a wide variety of adverse effects. Clozapine is not the first-line drug of choice due to its range of adverse effects, making compliance an issue for many patients.
Clozapine was first synthesized in 1956 in many European countries like Switzerland, Austria, West Germany, and Finland. Concurrent studies in the United States led to reports of death due to cases of agranulocytosis, taking clozapine off the market for a long time. A pivotal study known as the US Clozaril Study showed the efficacy of clozapine over chlorpromazine in a 6-week trial of patients who failed to respond to 3 previous antipsychotic drugs. The results of the study ultimately led to the FDA approval for treatment-resistant schizophrenia. A meta-analysis done in 2018 showed that clozapine might be more effective than other antipsychotics even when used as a first- or second line of treatment.
Regarding suicide risk, clozapine has been shown to reduce suicidal behavior even in patients with non-treatment-resistant schizophrenia and schizoaffective disorder.
Clozapine is part of a group of drugs known as second-generation antipsychotics or atypical antipsychotics. Antipsychotic drugs are key in treating the core symptoms of schizophrenia: hallucinations and delusions. As an atypical antipsychotic, clozapine acts an antagonist to both dopamine and serotonin receptors. It binds to the dopamine D4 with higher affinity than dopamine D2 receptor contributing to the decrease in negative symptoms and extrapyramidal symptoms. Clozapine is a partial 5-HT1A agonist, contributing to the reduction of negative symptoms and extrapyramidal symptoms, and a muscarinic M1, M2, M3, M5, histamine, and alpha-1 adrenergic-receptor antagonist. Norclozapine, the metabolite of clozapine, actively works on the M1 and M4 receptors.
Clozapine is metabolized to norclozapine and other metabolites by the cytochrome P450 enzymes (CYP1A2, CYP3A4, CYP2C19, with some influence of CYP2C9 and CYP2D6). Clozapine has a short plasma half-life of 12 to 16 hours.
According to the FDA, clozapine is available as a regular oral pill and orally disintegrating tablets with a recommended dosage of up to 900 mg per day. The average dose is 300 mg per day for women and 400 mg per day for men. A slow titration is important for reducing the many side effects associated with clozapine. With the persistent partial response, clozapine may be augmented with ECT to increase the efficacy of the drug. Other methods of augmentation include lamotrigine and other antipsychotics.
The risk of developing agranulocytosis is around 1% in patients who take clozapine, and this may be independent of dosing. Most cases occur early in the treatment, within 6 weeks to 6 months, and require extensive monitoring of blood absolute neutrophil counts. Neutropenia is defined as an ANC level below 1500/mm and agranulocytosis is defined as an ANC level below 500/mm. Many have tried to explain the link between clozapine and agranulocytosis by attributing this adverse effect to drug interactions with the immune system and genetic predisposition. A study in 2015 looked into the benefits of pharmacogenetic testing and how it may affect monitoring in patients at risk for clozapine-induced agranulocytosis. The study suggested that patients with a lower genetic risk may benefit from a more relaxed hematological monitoring schedule. Risk factors include old age, female, genetics, and concurrent treatment with other drugs known to cause agranulocytosis. Patients taking clozapine are required to be placed on a national registry. Granulocyte colony-stimulating factor may be used to increase levels of white blood cells.
Clozapine-induced myocarditis is a rare complication, affecting less than 3% of patients. This lethal dose-independent side effect appears more frequently appears during the first 4 weeks of treatment. Signs and symptoms of myocarditis in these patients may have a high variability from having a flu-like illness to respiratory and cardiovascular symptoms. Some cases of clozapine-induced myocarditis may even present in an atypical form without any symptoms leading to higher rates of fatality. Risk factors include rapid titration of the drug, metabolic side effects of clozapine, concurrent use of selective serotonin reuptake inhibitors and illicit substances. Treatment includes immediate clozapine cessation which may resolve the case.
Clozapine is associated with significant weight gain, diabetes type 2, diabetic ketoacidosis, and increased lipid levels-all due to increased insulin resistance. Both clozapine and olanzapine are known to have higher metabolic side effects compared to the other atypical and typical antipsychotics due to their high affinity for serotonin 5-HT2C receptors. It is important to note that other factors including poor diet and a sedentary lifestyle may contribute to the development of metabolic syndrome. The American Heart Association defines metabolic syndrome as increased weight, dyslipidemia, increased blood pressure, increased glucose intolerance, increased proinflammatory and prothrombic states. The development of DKA is one of the serious side effects of clozapine, having a higher mortality rate compared to agranulocytosis. Recommendations include counseling the patient on proper diet, exercise and other drugs like metformin and orlistat to reduce the metabolic effects of clozapine.
Clozapine may lower the seizure threshold in both epileptic and normal patients. The risk is usually dose-dependent, around 1% to 6%, especially with rapid titration and may be more prevalent in younger patients. This side effect may appear at any stage of treatment. Patients who experience a seizure while on clozapine may benefit from the addition on an anti-epileptic like valproic acid.
In a recent study, clozapine, when compared to several other antipsychotics, was the only drug to increase platelet adhesion and aggregation The risk seems to be higher in elderly patients and pregnant women taking high doses. Many studies have found this link to be dose independent, highly lethal and have an early onset.
Cholinergic and serotonergic properties of clozapine may affect the gastrointestinal system and lead to constipation or even ileus. Constipation affects anywhere from 15% to 60% of all patients taking clozapine and is dose-dependent, making it one of the most common side effects. In severe cases, constipation can progress to ileus which may lead to bowel obstruction and bowel ischemia. One study suggests these cholinergic effects may even lead to dysphagia which can progress to aspiration pneumonia, suggesting gastric hypomotility may not be limited to just the bowel. Management includes adequate fluid intake, laxative or docusate use, and reduction in dose.
Other side effects may include orthostatic hypotension, sedation, tachycardia, sexual dysfunction, and urinary retention.
FDA states the following Black Box warnings:
Drugs that may inhibit cytochrome CYP1A2 leading to increased levels of clozapine include but are not limited to antifungals, oral contraceptives, fluvoxamine, ciprofloxacin, caffeine disulfiram. Drugs that may induce CYP1A2 include but are not limited to omeprazole, rifampicin, tobacco, phenytoin, and phenobarbital. Other drugs that induce (carbamazepine and rifampicin) and inhibit (cimetidine and erythromycin, among others) CYP3A4 may also affect clozapine drug levels.
Tobacco may affect clozapine metabolism through CYP1A2; therefore, it is important to understand the blood levels and efficacy of clozapine when a patient smokes or when they abruptly stop.
Serious side effects that need to be monitored include but are not limited to:
Weekly complete blood count (CBC) to measure ANC levels. ANC levels less than 1500 indicate neutropenia. Levels less than 500 indicate agranulocytosis. Complete blood count should be taken weekly for the first 6 months, then every other week for the next 6 months. A national registry is in place to monitor for safe use.
Diet and exercise, blood glucose levels
Baseline troponin I or T levels, high sensitivity CRP levels, echocardiography, and BNP levels, as well as vitals and weekly laboratory testing of troponins, CRP, and BNP levels
EEG and clozapine blood levels
Clozapine, due to its many lethal adverse reactions, has become a drug that many clinicians are afraid to prescribe due to fear of patient safety. One of the greatest fears for clozapine is the side effect of agranulocytosis. The FDA has required a registry to be in place to monitor weekly white blood cell count levels for anyone prescribed with clozapine. There are many limitations for clozapine use as described in a systematic review looking at barriers to its use. There are 3 levels this study uses to describe the barriers and they are patient, clinician, and health-system related barriers. Some patient barriers include non-compliance to weekly blood draws, tolerating clozapine side effects, and patients prescribed multiple drugs. From the clinician’s point of view, some barriers include, inadequate inexperience and knowledge of clozapine, fear of side effects, lack of adherence to guidance, need for intense monitoring, and perception of patient non-compliance. Some systemic problems include not enough resources including staffing and nurses, shortage of beds, and service fragmentation. The use of POC devices, educational interventions for clinicians and patients, and shared decision-making involving patients are crucial to tackling these barriers. These solutions need to be evaluated using controlled study designs. (Level IV)
Coordination of clozapine’s care is best done through the national registry which helps with identifying the patient and coordinating with the prescriber and pharmacy.
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